Devices and methods for selectively lysing cells

ABSTRACT

A device for generating microbubbles in a gas and liquid mixture and injection device, the device comprising: a housing defining a mixing chamber; means for mixing solution contained in the mixing chamber to generate microbubbles in the solution; a needle array removably attached to the housing and in fluid connection with the mixing chamber, the needle array including at least one needle; and at least one pressure sensor for measuring tissue apposition pressure, the pressure sensor being mounted on one of the housing and the needle array.

CLAIM FOR PRIORITY/REFERENCE TO CO PENDING APPLICATIONS

This application claims priority to U.S. Utility patent application Ser.No. 11/515,634 filed Sep. 5, 2006, U.S. Utility patent application Ser.No. 11/334,794 filed Jan. 17, 2006, U.S. Utility patent application Ser.No. 11/334,805 filed Jan. 17, 2006, and U.S. Utility patent applicationSer. No. 11/292,950 filed Dec. 2, 2005, the entirety of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a microbubble generation device and asystem for selectively lysing cells by cavitating microbubbles.

BACKGROUND OF THE INVENTION

Gynoid lipodystrophy is a localized metabolic disorder of thesubcutaneous tissue which leads to an alteration in the topography ofthe cutaneous surface (skin), or a dimpling effect caused by increasedfluid retention and/or proliferation of adipose tissue in certainsubdermal regions. This condition, commonly known as cellulite, affectsover 90% of post-pubescent women, and some men. Cellulite commonlyappears on the hips, buttocks and legs, but is not necessarily caused bybeing overweight, as is a common perception. Cellulite is formed in thesubcutaneous level of tissue below the epidermis and dermis layers. Inthis region, fat cells are arranged in chambers surrounded by bands ofconnective tissue called septae. As water is retained, fat cells heldwithin the perimeters defined by these fibrous septae expand and stretchthe septae and surrounding connective tissue. Furthermore, adipocyteexpansion from weight gain may also stretch the septae. Eventually thisconnective tissue contracts and hardens (scleroses) holding the skin ata non-flexible length, while the chambers between the septae continue toexpand with weight gain, or water gain. This results in areas of theskin being held down while other sections bulge outward, resulting inthe lumpy, “orange peel” or “cottage-cheese” appearance on the skinsurface.

Even though obesity is not considered to be a root cause of cellulite,it can certainly worsen the dimpled appearance of a cellulitic regiondue to the increased number of fat cells in the region. Traditional fatextraction techniques such as liposuction that target deep fat andlarger regions of the anatomy, can sometimes worsen the appearance ofcellulite since the subdermal fat pockets remain and are accentuated bythe loss of underlying bulk (deep fat) in the region. Many timesliposuction is performed and patients still seek therapy for remainingskin irregularities, such as cellulite.

A variety of approaches for treatment of skin irregularities such ascellulite and removal of unwanted adipose tissue have been proposed. Forexample, methods and devices that provide mechanical massage to theaffected area, through either a combination of suction and massage orsuction, massage and application of energy, in addition to applicationof various topical agents are currently available. Developed in the1950's, mesotherapy is the injection of various treatment solutionsthrough the skin that has been widely used in Europe for conditionsranging from sports injuries to chronic pain, to cosmetic procedures totreat wrinkles and cellulite. The treatment consists of the injection ortransfer of various agents through the skin to provide increasedcirculation and the potential for fat oxidation, such as aminophylline,hyaluronic acid, novocaine, plant extracts and other vitamins. Thetreatment entitled Acthyderm (Turnwood International, Ontario, Canada)employs a roller system that electroporates the stratum corneum to opensmall channels in the dermis, followed by the application of variousmesotherapy agents, such as vitamins, antifibrotics, lypolitics,anti-inflammatories and the like.

Massage techniques that improve lymphatic drainage were tried as earlyas the 1930's. Mechanical massage devices, or Pressotherapy, have alsobeen developed such as the “Endermologie” device (LPG Systems, France),the “Synergie” device (Dynatronics, Salt Lake City, Utah) and the“Silklight” device (Lumenis, Tel Aviv, Israel), all utilizing subdermalmassage via vacuum and mechanical rollers. Other approaches haveincluded a variety of energy sources, such as Cynosure's “TriActive”device (Cynosure, Westford, Mass.) utilizing a pulsed semiconductorlaser in addition to mechanical massage, and the “Cellulux” device(Palomar Medical, Burlington, Mass.) which emits infrared light througha cooled chiller to target subcutaneous adipose tissue. The “VelaSmooth”system (Syneron, Inc., Yokneam Illit, Israel) employs bipolarradiofrequency energy in conjunction with suction to increase metabolismin adipose tissue, and the “Thermacool” device (Thermage, Inc., Hayward,Calif.) utilizes radiofrequency energy to shrink the subdermal fibrousseptae to treat wrinkles and other skin defects. Other energy basedtherapies such as electrolipophoresis, using several pairs of needles toapply a low frequency interstitial electromagnetic field to aidcirculatory drainage have also been developed. Similarly, non-invasiveultrasound is used in the “Dermosonic” device (Symedex Medical,Minneapolis, Minn.) to promote reabsorption and drainage of retainedfluids and toxins.

Another approach to the treatment of skin irregularities such asscarring and dimpling is a technique called subcision. This techniqueinvolves the insertion of a relatively large gauge needle subdermally inthe region of dimpling or scarring, and then mechanically manipulatingthe needle below the skin to break up the fibrous septae in thesubdermal region. In at least one known method of subcision, a localanesthetic is injected into the targeted region, and an 18 gauge needleis inserted 10-20 mm below the cutaneous surface. The needle is thendirected parallel to the epidermis to create a dissection plane beneaththe skin to essentially tear through, or “free up” the tightened septaecausing the dimpling or scarring. Pressure is then applied to controlbleeding acutely, and then by the use of compressive clothing followingthe procedure. While clinically effective in some patients, pain,bruising, bleeding and scarring can result. The known art also describesa laterally deployed cutting mechanism for subcision, and a techniqueemploying an ultrasonically assisted subcision technique.

Certain other techniques known as liposuction, tumescent liposuction,lypolosis and the like, target adipose tissue in the subdermal and deepfat regions of the body. These techniques may include also removing thefat cells once they are disrupted, or leaving them to be resorbed by thebody's immune/lymphatic system. Traditional liposuction includes the useof a surgical cannula placed at the site of the fat to be removed, andthen the use of an infusion of fluids and mechanical motion of thecannula to break up the fatty tissue, and suction to “vacuum” thedisrupted fatty tissue directly out of the patient.

The “Lysonix” system (Mentor Corporation, Santa Barbara, Calif.)utilizes an ultrasonic transducer on the handpiece of the suctioncannula to assist in tissue disruption (by cavitation of the tissue atthe targeted site). Liposonix (Bothell, Wash.) and Ultrashape (TelAviv,Israel) employ the use of focused ultrasound to destroy adipose tissuenoninvasively. In addition, cryogenic cooling has been proposed fordestroying adipose tissue. A variation on the traditional liposuctiontechnique known as tumescent liposuction was introduced in 1985 and iscurrently considered by some to be the standard of care in the UnitedStates. It involves the infusion of tumescent fluids to the targetedregion prior to mechanical disruption and removal by the suctioncannula. The fluids may help to ease the pain of the mechanicaldisruption, while also swelling the tissues making them more susceptibleto mechanical removal. Various combinations of fluids may be employed inthe tumescent solution including a local anesthetic such as lidocaine, avasoconstrictive agent such as epinephrine, saline, potassium and thelike. The benefits of such an approach are detailed in the articles,“Laboratory and Histopathologic Comparative Study of InternalUltrasound-Assisted Lipoplasty and Tumescent Lipoplasty” Plastic andReconstructive Surgery, Sep. 15, (2002) 110:4, 1158-1164, and “When OneLiter Does Not Equal 1000 Milliliters: Implications for the TumescentTechnique” Dermatol. Surg. (2000) 26:1024-1028, the contents of whichare expressly incorporated herein by reference in their entirety.

Various other approaches employing dermatologic creams, lotions,vitamins and herbal supplements have also been proposed to treatcellulite. Private spas and salons offer cellulite massage treatmentsthat include body scrubs, pressure point massage, essential oils, andherbal products using extracts from plant species such as seaweed,horsetail and clematis and ivy have also been proposed. Although amultitude of therapies exist, most of them do not provide a lastingeffect on the skin irregularity, and for some, one therapy may cause theworsening of another (as in the case of liposuction causing scarring ora more pronounced appearance of cellulite). Yet other treatments forcellulite have negative side effects that limit their adoption. Mosttherapies require multiple treatments on an ongoing basis to maintaintheir effect at significant expense and with mixed results.

Medical ultrasound apparatus and methods are generally of two differenttypes. One type of medical ultrasound wave generating device known inthe art is that which provides high intensity focused ultrasound or highacoustic pressure ultrasound for tissue treatment, for example for tumordestruction. High intensity or high acoustic pressure ultrasound iscapable of providing direct tissue destruction. High intensity or highacoustic pressure ultrasound is most commonly focused at a point inorder to concentrate the energy from the generated acoustic waves in arelatively small focus of tissue. However, another type of medicalultrasound is a lower intensity and less focused type of ultrasound thatis used for diagnostic imaging and physical therapy applications. Lowacoustic pressure ultrasound is commonly used, for example, for cardiacimaging and fetal imaging. Low acoustic pressure ultrasound may be usedfor tissue warning, without tissue disruption, in physical therapyapplications. Low acoustic pressure ultrasound, using power ranges fordiagnostic imaging, generally will not cause any significant tissuedisruption when used for limited periods of time in the absence ofcertain enhancing agents.

Methods and apparatus of using high intensity focused ultrasound todisrupt subcutaneous tissues directly has been described in the knownart. Such techniques may utilize a high intensity ultrasound wave thatis focused on a tissue within the body, thereby causing a localizeddestruction or injury to cells. The focusing of the high intensityultrasound may be achieved utilizing, for example, a concave transduceror an acoustic lens. Use of high intensity focused ultrasound to disruptfat, sometimes in combination with removal of the fat by liposuction,has been described in the known prior art. Such use of high intensityfocused ultrasound should be distinguished from the low acousticpressure ultrasound.

In light of the foregoing, it would be desirable to provide methods andapparatus for treating skin irregularities such as cellulite and toprovide a sustained aesthetic result to a body region, such as the face,neck, arms, legs, thighs, buttocks, breasts, stomach and other targetedregions which are minimally or non-invasive. It would also be desirableto provide methods and apparatus for treating skin irregularities thatenhance prior techniques and make them less invasive and subject tofewer side effects.

Therefore, there has been recognized by those skilled in the art a needfor an apparatus and method for the use of low intensity ultrasound totreat subcutaneous tissues. Use of low intensity ultrasound, in thepower ranges of diagnostic ultrasound, would be safer to use, have fewerside effects, and could be used with less training. The presentinvention fulfills these needs and others.

SUMMARY OF THE INVENTION

Disclosed is a device for generating microbubbles in a gas and liquidmixture and injection device, which includes a housing defining a mixingchamber; means for mixing solution contained in the mixing chamber togenerate microbubbles in the solution; and a needle array removablyattached to the housing and in fluid connection with the mixing chamber,the needle array including at least one needle.

The mixing chamber may include a first mixing chamber in fluidcommunication with a second mixing chamber. Moreover, the mixing meansmay include means for expressing a solution of fluid and gas between thefirst and second mixing chambers to generate microbubbles in thesolution.

The device may further include a fluid reservoir in fluid connectionwith at least one of the first and second mixing chambers; and a sourceof gas in fluid connection with at least one of the first and secondmixing chambers. Optionally, the fluid reservoir and/or the mixingchamber(s) may be thermally insulated and/or include means formaintaining the fluid at a predetermined temperature. Still further, thesource of gas may be room air, or may include air, oxygen, carbondioxide, perfluoropropane or the like which may be maintained at greaterthan atmospheric pressure.

The solution expressing means may include first and second pistonsmounted for reciprocation within the first and second mixing chambers.

Still further, the device may include means for reciprocating the firstand second pistons to express fluid and gas between the first and secondcylinders to create a microbubble solution. The reciprocating means maybe a source of compressed air; and the first and second cylinders may bepneumatic cylinders.

The device may include a needle deployment mechanism operably connectedto the needle array for deploying the at least one needle(s) between aretracted and an extended position. The needle array may include atleast two needles and the needle deployment mechanism selectivelydeploys one or more of the at least two needles between the retractedand the extended position. Still further, the needle deploymentmechanism may include at least one of a pneumatic piston, an electricmotor, and a spring.

The device may include at least one pressure sensor for measuring tissueapposition pressure. The sensor may be provided on either or both of thehousing and the needle array. Deployment of the at least one needle maybe inhibited if a measured apposition pressure values falls beneath aninitial threshold value or exceeds a secondary threshold value. Thedevice may include two or more sensors wherein deployment of the atleast one needle is inhibited if a difference in measured appositionpressure values between any two sensors exceeds a threshold value.

The aforementioned mixing means may include at least one of a blade,paddle, whisk, and semi-permeable membrane positioned within the mixingchamber. The mixing means may further include one of a motor and apneumatic source operably coupled to the at least one of a blade,paddle, whisk, and semi-permeable membrane.

The device of the present invention may include tissue apposition meansfor pulling the needle array into apposition with tissue. The tissueapposition means may include at least one vacuum orifice defined in atleast one of the housing and the needle array, whereby the vacuumorifice transmits suction from a source of partial vacuum to tissuebringing the needle array into apposition with the tissue. The vacuumorifice may be formed in the needle array, and the at least one needlemay be positioned within the vacuum orifice. Still further, the vacuumorifice may define a receptacle, whereby tissue is pulled at leastpartially into the receptacle when the vacuum orifice transmits suctionfrom the source of partial vacuum.

In some embodiments, the needle array includes a tissue appositionsurface; and the tissue apposition means further includes at least oneflange mounted on the tissue apposition surface and surrounding thevacuum orifice.

The device of the present invention may include means for adjusting aneedle insertion depth of the at least one needle. The needle array mayinclude at least two needles and the insertion depth adjustment meansmay individually adjust the insertion depth of each needle. In oneembodiment, the needle insertion depth adjustment means may include aplurality of discrete needle adjustment depths. Alternatively, theneedle insertion depth adjustment means provides continuous adjustmentof the needle adjustment depth. Still further, the needle insertiondepth adjustment means may include a readout and/or a display indicativeof the needle adjustment depth.

According to one embodiment, the needle array includes a tissueapposition surface; and the at least one needle includes a distal end,the at least one needle being moveable between a retracted position inwhich the distal end of the needle is maintained beneath the tissueapposition surface and an extended position in which the distal end ofthe needle extends beyond the tissue apposition surface.

According to one embodiment an ultrasound transducer is operablyconnected to one of the needle array, the housing and the at least oneneedle.

According to one aspect, the needle array may generally surround theultrasound transducer. Alternatively, the ultrasound transducer maygenerally surround the needle array. Moreover, the ultrasound transducermay be integrally formed with the needle array.

The device may further include a fluid pressurization mechanism in fluidcommunication with the at least one needle.

Still further, the device may include means for controlling a volume andpressure of fluid dispensed from the fluid reservoir into the mixingchamber. Moreover the device may include means for controlling thevolume, pressure, and rate at which fluid or solution is injected intothe tissue.

A machine readable identifier may be provided on the needle array. Theidentifier may be used to uniquely identify the ultrasound transducer,needle array and/or characteristics of the needle array.

According to one embodiment, the device includes a machine readableidentifier on the needle array and means for reading the identifieroperably connected to the needle deployment mechanism. Optionally, theneedle deployment mechanism inhibits deployment of the at least oneneedle unless the identifier reading means authenticates the identifier.Moreover, the needle deployment mechanism may optionally accumulate thenumber of times the needle array associated with a given identifier isdeployed and inhibit deployment of the at least one needle if theaccumulated number needle deployments associated with the identifierexceeds a predetermined value.

According to one embodiment, the device includes a machine readableidentifier on the needle array and means for reading the identifieroperably connected to the fluid pressurization mechanism, wherein thefluid pressurization mechanism adjusts the fluid injection pressure inresponse to information read from the identifier.

Also disclosed is a system comprising, a container containing a measuredamount of a solution including at least one of a vasoconstrictor, asurfactant, and an anesthetic, the solution comprising a liquid and atleast one of a gas and a fluid; a needle array in fluid connection withthe container, the needle array including at least one needle. The gasis at least partially dissolved and may be fully dissolved in the fluid.Optionally, the solution container is enclosed, and the solution ismaintained at greater than atmospheric pressure.

The aforementioned system may include an ultrasound transducer apparatuscapable of operating in at least one of first, second, third, and fourthenergy settings, wherein the first energy setting is selected tofacilitate the absorption of solution by the tissue, the second energysetting is selected to facilitate stable cavitation, the third energysetting is selected to facilitate transient cavitation, and the fourthenergy setting is selected to facilitate pushing bubbles within tissue.The transducer apparatus may include first and second transducers,wherein the first transducer facilitates popping of bubbles and thesecond transducer facilitates bringing dissolved gas out of solution.According to one embodiment, the transducer apparatus produces at leastone of unfocussed and defocused ultrasound waves.

Also disclosed is a method for selectively lysing cells, comprising:percutaneously injecting a solution including at least one of avasoconstrictor, a surfactant, and an anesthetic into subcutaneoustissue, insonating the tissue with ultrasound setting to distribute thesolution by acoustic radiation force; and insonating the tissue at asecond ultrasound setting to induce cell uptake of the solution andthereby lyse the cells.

Also disclosed is a method for selectively lysing cells, comprising:percutaneously injecting a microbubble solution into subcutaneoustissue; insonating the tissue at a first ultrasound setting todistribute the solution and push the microbubble against walls of thecells by acoustic radiation force; and insonating the tissue at a secondultrasound setting to induce transient cavitation. The solution mayinclude at least one of a vasoconstrictor, a surfactant, and ananesthetic.

Also disclosed is a method for selectively lysing cells, comprising:percutaneously injecting a solution into subcutaneous tissue, thesolution containing at least one of a dissolved gas and a partiallydissolved gas; insonating the tissue to induce stable cavitation andgenerate microbubbles; insonating the tissue with ultrasound todistribute the solution and push the microbubble against walls of thecells by acoustic radiation force; insonating the tissue with ultrasoundto induce transient cavitation. The solution may include at least one ofa vasoconstrictor, a surfactant, and an anesthetic.

Each of the aforementioned embodiments may include a needle or needleshaving a texture encouraging the creation of microbubbles.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description, in which:

FIGS. 1A and 1B are block diagrams of a bubble generator according tothe present invention;

FIG. 1C is a block diagram of a first modification of the bubblegenerator of FIG. 1B;

FIG. 1D is a block diagram of a second modification of the bubblegenerator of FIG. 1B;

FIG. 2 is a block diagram of a tissue cavitation system according to thepresent invention;

FIGS. 3A-3C are views of a fluid injection device including a manifoldand an injection depth adjustment mechanism according to the presentinvention;

FIG. 3D shows a modified mechanism for adjusting the injection depth ofthe fluid injection device of FIG. 3A;

FIGS. 4A-4C show an alternate embodiment fluid injection deviceincluding a mechanism for individually adjusting the fluid flow througheach needle and a mechanism for individually adjusting the injectiondepth;

FIG. 5 shows a needle array including an optional sensor used in a fluidinjection device according to the present invention;

FIGS. 6A and 6B show straight and side firing needles used in the needlearray of FIG. 5;

FIG. 7 is a block diagram a fluid injection device including a mechanismfor rotating the needle in situ;

FIGS. 8A and 8B show the fluid injection device in a retracted and fullyextended position;

FIGS. 9A-9C show a tissue apposition mechanism according to the presentinvention;

FIGS. 10A and 10B show an alternate embodiment bubble generator and asystem for injecting and insonating bubbles using the same;

FIG. 11 shows a counterbalance arm for supporting a solution injectionand insonation system according to the present invention;

FIGS. 12A and 12B show a handpiece including a fluid injection mechanismused as part of a solution injection and insonation system of thepresent invention;

FIG. 13 is a block diagram of an alternate embodiment of the tissuecavitation system which does not utilize a bubble generator; and

FIG. 14 is a section view of a transducer apparatus according to thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

One aspect of the present invention relates to a device for generating amicrobubble solution and for a system using the device to selectivelylyse tissue.

According to a first embodiment of the invention the microbubblesolution includes a fluid or mixture containing one or more of thefollowing: active bubbles, partially dissolved bubbles, a saturated orsupersaturated liquid containing fully dissolved bubbles or amaterial/chemical which generates bubbles in situ. The bubbles may beencapsulated within a lipid or the like, or may be unencapsulated (free)bubbles.

Active bubbles refer to gaseous or vapor bubbles which may includeencapsulated gas or unencapsulated gas. These active bubbles may or maynot be visible to the naked eye. Dissolved bubbles refer to gas whichhas dissolved into the liquid at a given pressure and temperature butwhich will come out of solution when the temperature and/or pressure ofthe solution changes or in response to ultrasound insonation. Themicrobubbles may come out of solution in situ, i.e., after the solutionis injected into the tissue. This may, for example, occur when thesolution reaches the temperature of the tissue or when the tissue issubjected to ultrasound insonation. Alternatively, the microbubble maycome out of solution before the solution is injected into the tissuewhen reaching atmospheric pressure. Thus, the bubbles may come out ofsolution before or after the solution is injected into the tissue.

As noted, the solution includes a liquid (fluid) and a gas which may ormay not be dissolved in the liquid. By manner of illustration, theliquid portion of enhancing agent may include an aqueous solution,isotonic saline, normal saline, hypotonic saline, hypotonic solution, ora hypertonic solution. The solution may optionally include one or moreadditives/agents to raise the pH (e.g., sodium bicarbonate) or abuffering agent such as known in the art. By manner of illustration thegaseous portion of the solution may include air drawn from the room(“room air” or “ambient air”), oxygen, carbon dioxide, perfluoropropane,argon, hydrogen, or a mixture of one or more of these gases. However,the invention is not limited to any particular gas. There are a numberof candidate gas and liquid combinations, the primary limitation beingthat both the gas and the liquid must be biocompatible, and the gas mustbe compatible with the liquid.

According to a presently preferred embodiment the liquid portion of themicrobubble solution includes hypotonic buffered saline and the gaseousportion includes air.

It should be noted that the biocompatibility of overall solution dependson a variety of factors including the biocompatibility of the liquid andgas, the ratio of gas to liquid, and the size of the microbubbles. Ifthe microbubbles are too large they may not reach the target tissue.Moreover, if the bubbles are too small they may go into solution beforethey can be used therapeutically. As will be explained in further detailbelow, the microbubble solution of the present invention may include adistribution of different sized microbubbles. Thus it is anticipatedthat the solution may contain at least some microbubbles which are toosmall to be therapeutically useful as well as some which are larger thanthe ideal size. It is anticipated that a filter, filtering mechanism orthe like may be provided to ensure that bubbles larger than a thresholdsize are not injected into the tissue.

It should further be appreciated that “biocompatible” is a relative termin that living tissue may tolerate a small amount of a substance whereasa large amount of the same substance may be toxic with both dose anddosage as considerations. Thus, the biocompatibility of the microbubblesolution of the present invention should be interpreted in relation tothe amount of solution being infused, the size of the microbubbles, andthe ratio of gas to liquid. Moreover, since selective cell lysis is oneof the objects of the present invention, the term biocompatible shouldbe understood to include a mixture or solution which may result inlocalized cell lysis alone or in conjunction with ultrasound insonation.

The microbubble solution according to the present invention may includeone or more additives such as a surfactant to stabilize themicrobubbles, a local anesthetic, a vasodilator, and a vasoconstrictor.By manner of illustration the local anesthetic may be lidocaine and thevasoconstrictor may be epinephrine. Table 1 is a non-exclusive list ofother vasoconstrictors which may be included in the microbubble solutionof the present invention. Table 2 is a non-exclusive list of other localanesthetics which may be included in the microbubble solution of thepresent invention. Table 3 is a non-exclusive list of gaseousanesthetics which may be included in the gaseous portion of the solutionof the present invention. Table 4 is a non-exclusive list of surfactantswhich may be included in the solution of the present invention.

TABLE 1 Vasoconstrictors Norepinephrine Epinephrine Angiotensin IIVasopressin Endothelin

TABLE 2 Anesthetics (Local) Amino esters Benzocaine ChloroprocaineCocaine Procaine Tetracaine Amino amides Bupivacaine LevobupivacaineLidocaine Mepivacaine Prilocaine Ropivacaine Articaine Trimecaine

TABLE 3 Anesthetics (gaseous) Halothane Desflurane SevofluraneIsoflurane Enflurane

TABLE 4 Surfactants Anionic (based on sulfate, sulfonate or carboxylateanions)    Sodium dodecyl sulfate (SDS), ammonium lauryl sulfate,    andother alkyl sulfate salts    Sodium laureth sulfate, also known assodium lauryl ether    sulfate (SLES)    Alkyl benzene sulfonate   Soaps, or fatty acid salts Cationic (based on quaternary ammoniumcations)    Cetyl trimethylammonium bromide (CTAB) a.k.a. hexadecyl   trimethyl ammonium bromide, and other    alkyltrimethylammonium salts   Cetylpyridinium chloride (CPC)    Polyethoxylated tallow amine (POEA)   Benzalkonium chloride (BAC)    Benzethonium chloride (BZT)Zwitterionic (amphoteric)    Dodecyl betaine    Dodecyl dimethylamineoxide    Cocamidopropyl betaine    Coco ampho glycinate Nonionic Alkylpoly(ethylene oxide) called Poloxamers or Poloxamines) Alkylpolyglucosides, including:    Octyl glucoside    Decyl maltoside Fattyalcohols    Cetyl alcohol    Oleyl alcohol Cocamide MEA, cocamide DEA,cocamide TEA

The enhancing solution may further include a buffering agent such assodium bicarbonate. Table 5 is a non-exclusive list of buffers which maybe included in the solution of the present invention.

TABLE 5 Buffer H₃PO₄/NaH₂PO₄ (pK_(a1)) NaH₂PO₄/Na₂HPO₄ (PK_(a2))1,3-Diaza-2,4-cyclopentadiene and GlyoxalineN-Tris(hydroxymethyl)methyl-2- (Imidazole) aminoethanesulfonic acid(TES) ampholyte N-(2-hydroxyethyl) piperazine-N′-2-N-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic hydroxypropanesulfonicacid (HEPPSO) acid (HEPES) Acetic acid Citric acid (pK_(a1))N-Tris(hydroxymethyl)methyl-3- Triethanolamine(2,2′,2″-Nitrilotriethanol aminopropanesulfonic acid (TAPS)Tris(2-hydroxyethyl)amine) Bis(2- N-[Tris(hydroxymethyl)methyl]glycine,3-[(3- hydroxyethyl)iminotris(hydroxymethyl)methaneCholamidopropyl)dimethylammonio]propanesulfonic (Bis-Tris) acid(Tricine) Cacodylic acid 2-Amino-2-(hydroxymethyl)-1,3-propanediol(Tris) H₂CO₃/NaHCO₃ (pK_(a1)) Glycine amide Citric acid (pK_(a3))N,N-Bis(2-hydroxyethyl)glycine (Bicine) 2-(N-Morpholino)ethanesulfonicAcid (MES) Glycylglycine (pK_(a2)) N-(2-Acetamido)iminodiacetic Acid(ADA) Citric acid (pK_(a2)) Bis-Tris Propane (pK_(a1)) Bis-Tris Propane(pK_(a2)) Piperazine-1,4-bis(2-ethanesulfonic acid)N-(2-Acetamido)-2-aminoethanesulfonic acid (PIPES) (ACES) Boric acid(H₃BO₃/Na₂B₄O₇) N-Cyclohexyl-2-aminoethanesulfonic acid (CHES Glycine(pK_(a1)) Glycine (pK_(a2)) N,N-Bis(2-hydroxyethyl)-2- NaHCO₃/Na₂CO₃(pK_(a2)) aminoethanesulfonic acid (BES) 3-Morpholinopropanesulfonicacid (MOPS) N-Cyclohexyl-3-aminopropanesulfonic acid (CAPS)Na₂HPO₄/Na₃PO₄ (pK_(a3)) Hexahydropyridine (Piperidine) *The anhydrousmolecular weight is reported in the table. Actual molecular weight willdepend on the degree of hydration.

It should be noted that like reference numerals are intended to identifylike parts of the invention, and that dashed lines are intended torepresent optional components.

FIG. 1A depicts a first embodiment of a device 100 for generatingmicrobubbles in the enhancing solution. The device 100 consists of aliquid reservoir 102, a gas vapor reservoir 104 (shown in dashed lines)and a bubble generator 106. The bubble generator 106 is a vessel orvessels in which the fluid and gas are mixed. Fluid from the liquidreservoir 102 and gas/vapor from the gas reservoir 104 flow into thebubble generator 106 and are mixed to create microbubbles and/orsupersaturate the fluid.

The device 100 may include a fluid metering device 124 (shown in dashedlines) controlling the amount of fluid dispensed into the bubblegenerator 106 and/or a fluid metering device 126 (shown in dashed lines)controlling the amount of microbubble solution to be injected into thetissue. The device 100 may further include a gas metering device 128(shown in dashed lines) used to control the amount of gas dispensed intothe bubble generator 106. The device 100 depicted in FIG. 1A includesboth of the fluid metering devices 124 and 126 and the gas meteringdevice 128; however, in practice one or more of these devices may beeliminated. As noted previously, two or more components may beintegrated together. For example, the fluid metering device 124 may beintegrated into the fluid injection device 202.

FIG. 1B is a more detailed illustration of a first embodiment of thebubble generator 106 and includes a housing 108, a pair of cylinders 116interconnected by a pathway 118. At least one of the cylinders 116 is influid communication with the liquid reservoir 102, and at least one ofthe cylinders 116 is in fluid communication with the gas reservoir 104(which may be ambient environment). The fluid pathway 118 provides fluidcommunication between the cylinders 116.

One or more of the cylinder(s) 116 may be provided with a reciprocatingpiston 120 driven by an external power source 122 such as a source ofcompressed air, spring, elastomeric member, motor, stepper motor or thelike. According to one embodiment, the reciprocating piston 120 is apneumatic piston manufactured by the Bimba Corporation.

Liquid from the liquid reservoir 102 may be pushed into the bubblegenerator 106 under positive pressure from an external pressurizationsource 110 (shown in dashed lines); it can be drawn into the bubblegenerator 106 under partial pressure which may for example be generatedby the reciprocating piston 120; or it can flow into the generator 106under gravity. Similarly, gas from the gas reservoir 104 may be pushedinto the bubble generator 106 under positive pressure from an externalpressurization source 112 (shown in dashed lines) or it can be drawninto the bubble generator 106 under partial pressure. As will bedescribed below, the piston 120 may also serve a dual purpose as a fluidpressurization mechanism for injecting the fluid into the tissue.

The bubble generator 106 may or may not be pressurized to enhance thesaturation of the gas in the solution or prevent dissolved gas fromcoming out of solution. An optional fluid pressurization mechanism 110(shown in dashed lines) may be used to maintain the fluid at a desiredpressurization. As will be described in further detail below, the fluidmay be chilled to further enhance solubility/saturation of the gas inthe solution.

FIG. 1C is an alternate embodiment of the microbubble generator 106,which utilizes a member 120′ (rotor) such as a blade, paddle, whisk,semi-permeable membrane or the like driven by an external power source122 to generate the microbubbles within a cylinder or mixing chamber(stator) 116. As will be appreciated by one of ordinary skill in the artthe member 120′ is rotationally driven by the external power source 122within a cylinder 116 or the like. An optional fluid pressurizationmechanism 130 may be used for injecting the fluid into the tissue.

The fluid in the reservoir 102 may be at ambient temperature.Alternatively, the fluid may be chilled slightly to enhance gassolubility (super saturation). The fluid reservoir 102 may be thermallyinsulated to maintain the fluid at its present temperature and or/thefluid reservoir 102 may include a heating/cooling mechanism (notillustrated) to maintain the fluid at a predetermined temperature.

If the gas used is air then the gas reservoir 104 may be eliminated infavor of simply drawing air from the environment, i.e., the room housingthe device 100 (“room air”). If room air is used, the device 100 mayinclude an air filter 114 (shown in dashed lines) such as a HEPA filteror the like.

FIG. 1D is an alternate embodiment of the microbubble generator 106,which utilizes an agitator 133 to agitate or shake a container orcartridge 132 containing measured amounts of liquid and gas and generatethe microbubbles within the cartridge 132. The microbubble solution isdispensed from the cartridge 132 to fluid injection device 202 (FIG. 2).Additionally, this cartridge 132 may incorporate an activeheating/cooling mechanism to control the temperature of the fluid at apredetermined setting. Furthermore, the cartridge 132 may bepressurized, such as by compressed air or mechanical mechanism to allowdispensation of the contents at a predetermined rate and pressure.

FIG. 2 is a block diagram of a liposculpture system 200 according to thepresent invention. The system 200 includes device 100, a fluid injectiondevice 202, an ultrasound transducer apparatus 204, an ultrasoundgenerator 206, an ultrasound control unit 208, and an injection controlunit 210. Device 100 may include the bubble generator 106 depicted inFIGS. 1A-1D or may be one of the alternative embodiments disclosedherein below.

The fluid injection device 202 may include a needle array 214 which mayinclude one or more needles 218. Alternatively, the fluid injectiondevice 202 may, for example, include one or more hypodermic syringes.

The fluid injection device 202 further includes or is operably connectedto a fluid pressurization mechanism 110 for pushing the solution intothe tissue. As noted above, the piston 120 or the like used to expressfluid between the cylinders 116 may serve as the fluid pressurizationmechanism 210.

One or more of the components collectively termed system 200 may becombined. For example the fluid injection device 202 may be integratedas a single component with the ultrasound transducer apparatus 204and/or the fluid injection control unit 210. Likewise, the ultrasoundcontrol unit 208 can be integrated as a single component with theultrasound generator 206. Such integration of components is contemplatedand falls within the scope of the present invention.

The fluid injection control unit 210 may control the amount of fluid andgas dispensed into the bubble generator 106 and/or the amount ofsolution injected into the tissue. Optionally, the control unit 210 maybe interfaced directly or indirectly with the fluid metering device(s)124, 126 and the gas metering device 128. The fluid injection controlunit 210 may control the mixing or agitation (if any) of the solutionwithin the bubble generator 106. The fluid injection control unit 210may control the injection of solution into the tissue 220 by theinjection device 202, including the deployment of a needle array 214,the depth to which the needle array 214 is deployed, and the amount ofsolution injected.

The fluid injection control unit 210 may control the individualdeployment and retraction of one more needles (or hypodermic syringes)of the needle array 214. Thus, the control unit 210 may deploy orretract the needles 218 (or hypodermic syringes) one at a time, maydeploy or retract two or more needles 218 at a time, or may deploy orretract all of the needles simultaneously.

Additionally, the fluid injection control unit 210 may individuallycontrol the amount of solution delivered to each needle 218. One ofordinary skill in the art will appreciate that there are many ways tocontrol the amount of solution delivered to each needle 218. Forexample, it may be desirable to deliver more solution in the center ofthe treatment area and less to the peripheral portion of the treatmentarea or vice-versa.

If the injection device 202 utilizes hypodermic syringes, then the fluidinjection control unit 210 may control the amount of fluid distributedto each syringe. As noted above it may be desirable to provide differingamounts of solution to different areas of the treatment area, and thismay be achieved by varying the amount of solution in each syringe.

As best seen in FIGS. 3A-3C, the fluid injection device 202 may includea manifold or fluid distribution pathway 212 (shown in dashed lines) influid connection with device 100 and needle array 214, and a needledeployment mechanism 216 operably connected to the needle array 214. Themanifold 212 is the fluid pathway used to transport the microbubblesolution from the microbubble generator 106 to the needle array 214.

One or more flow control devices 222 may be provided in the fluidpathway 212 to enable individualized control of the amount of fluiddispensed to each of the needles or syringes 218. The manifold 212 aloneor in combination with the flow control devices 222 controls thedistribution of the microbubble solution among the needles 218. Themanifold 212 may be configured to deliver a uniform amount of solutionto each of the needles 218 (or hypodermic syringes), or it may beconfigured to deliver differing amounts of solution to different needles218. The flow control devices 222 may be manually adjustable and/or maybe controlled by the injection control unit 210. An alternate embodimentmay include infinitely variable volume control at each needle orhypodermic through active means, such as with an electronic flow meterand controller.

It may be desirable to deploy all of the needles 218 simultaneously intothe tissue but deliver solution to one or more needles 218 individually.For example, it may be desirable to deliver solution sequentially togroups of one or more needles 218. If needles 218 are deployedindividually or in groups of two or more it may be desirable to deliversolution only to the deployed needles 218.

As will be explained below, the injection depth may be manuallydetermined by selecting an appropriate needle length or setting adesired injection depth.

The needle deployment mechanism 216 (FIGS. 2 and 3A) deploys one or moreneedles 218 (or hypodermic syringes) of the needle array 214 such thatneedles 218 penetrate a desired distance into the tissue. The needledeployment mechanism 216 may be configured to deploy the needle(s) 218to a fixed predetermined depth or may include means for adjusting thedepth that the needle(s) 218 are deployed.

There are several broad approaches for adjusting the injection depthwhich may be utilized. One way to adjust the injection depth is toprovide needle arrays 214 of varying length needles. According to thisembodiment, the user simply selects an array 214 having shorter/longerneedles 218 to achieve a desired injection depth. Moreover, thedifferent length needles 218 may be used within a given array 214.

According to another approach, the needle array 214 is displacedvertically in order to adjust the injection depth.

FIG. 3A shows aspects of an adjusting means, which may include a flange244A and a groove 244B arrangement for vertically adjusting the needlearray in discrete intervals.

FIG. 3D shows aspects of an adjusting means, which may include matingscrew threads 240 formed on the needle array 214 and the fluid injectiondevice 202 or housing 108 which enable the user to vertically adjust theneedle array 214 thereby altering the injection depth.

According to one embodiment, the injection depth may be continuouslyadjusted within a given range of injection depths. For example, the usermay be able to continually adjust the injection depth between 5 and 12millimeters by rotating the needle array 214. According to an alternateembodiment, the injection depth may be adjusted in discrete intervals.For example, the user may be able to adjust the injection depth between3 and 15 millimeters in 1 millimeter increments. In yet anotherembodiment, the needle depth may be controlled electronically wherebythe user enters a specified depth on the control unit 210.

The injection depth adjustment described above may specify the injectiondepth for the entire needle array 214. However, according to yet anotherapproach it may be desirable to facilitate the individualized adjustmentof one or more needles 218 of the needle array 214. The needledeployment mechanism 216 may allow for the independent adjustment of theinjection depth for one or more of the needles 218 or syringes.

One or more of the needles 218 or syringes may be displaced verticallyin order to adjust the injection depth of individual needles. Theadjustment of the injection depth (vertical needle displacement) may becontinuous or in discrete intervals, and may be manual or may beadjusted via the injection control unit 210.

As noted above, the injection depth may be adjusted by providing matingscrew threads 246 to dial in the desired injection depth (FIG. 4A), astandoff 248 to provide a means for adjusting the injection depth indiscrete intervals (FIG. 4B), or the like on the needle array 214 toadjust the vertical height of the needles 218 relative to the tissueapposition surface 226A.

Yet another approach to individualized injection depth control is todeploy individual needles or syringes 218 as opposed to deploying theentire needle array 214. The injection control unit 210 or needledeployment mechanism 216 selects the injection depth of each individualneedle or syringe 218 (FIG. 4C).

One of ordinary skill in the art will appreciate that there are manyother ways to implement the adjustment of the injection depth. Theinvention is not limited to the embodiments depicted in the drawings.

The needle deployment mechanism 216 deploys the needles 218 in responseto a signal from the fluid injection control unit 210. The deploymentmechanism 216 may include a spring, pneumatic ram, or the like whichdeploys the needles 218 with sufficient force to penetrate the tissue220. The fluid injection control unit 210 synchronizes the deploymentmechanism 216 with the injection of the microbubble solution into thetissue.

A predetermined amount of the solution may be injected at a singleinjection depth. Alternatively, the fluid injection control unit 210 insynchronism with the deployment mechanism 216 may inject solution ateach of plural injection depths, or may inject continuously as theneedle array 214 on either the forward (penetration) or rearward(withdrawal) strokes. It may be desirable to deploy the needles to afirst depth within the tissue and then retract the needles to a slightlyshallower injection depth before injecting the solution.

FIG. 5 is an enlarged view of the needle array 214 including at leastone hypodermic needle or micro-needle 218. The invention is not limitedto any particular length or gauge needle, and needles 218 are selectedin accordance with the depth of the tissue to be treated and toaccommodate patient comfort. Moreover, it may be desirable for theneedle array 214 to include needles of varying length and/or needles ofvarying gauge.

The embodiment depicted in FIG. 5 includes a plurality of uniformlyspaced needles 218. However, the scope of the invention is not limitedto any particular number of needles 218; moreover, the invention is notlimited to any particular geometric arrangement or configuration ofneedles 218. It may be desirable to have non-uniform needle spacing. Forexample, it may be desirable to have a smaller (denser) needle spacingin one portion of the treatment region and a greater (sparser) needlespacing in another portion. The use of additional needles 218 mayfacilitate uniform distribution of the microbubble solution in thetissue 220 and/or reduce the number of distinct injection cycles neededto treat a given area.

FIG. 6A depicts a needle 218 having a single injection orifice 242,which is linearly aligned with the needle shaft 224. The hypodermicneedle 218 is a tubular member having a lumen configured for injectionof the solution through the needle and into the tissue. The lumen mayinclude a textured surface for promoting the generation of microbubbles.

FIG. 6B depicts an alternative needle 218A having one or more sidefiring orifice(s) 242A which are generally orthogonal to longitudinalaxis of the shaft 224A. The side firing orifice(s) may be formed atdifferent heights along the length of the needle shaft such thatsolution is injected at varying injection depths. These orifice(s) mayalso be arranged in a specific radial pattern to preferentially directthe flow distribution.

Depending on the characteristics of the tissue undergoing treatment theuser may find that needle 218 is preferable over needle 218A or viceversa. Reference to the needles 218 should be understood to refergenerally to both the needles 218 (FIG. 6A) and the needles 218A (FIG.6B).

As shown in FIG. 7, some embodiments of the invention may include amechanism 256 for selectively rotating one or more of the needles 218 insitu. This feature may facilitate the uniform distribution of solutionin the tissue.

According to some embodiments of the invention it may be desirable forthe needle deployment mechanism 216 to ultrasonically vibrate one ormore of the needles 218. This feature may facilitate tissue penetrationand/or bringing dissolved gas out of solution. For example, anultrasound transducer 258 may be operably coupled to the needles 218and/or the needle array 214. The ultrasound transducer 258 is shown forthe sake of convenience in FIG. 7 however, the transducer 258 may beused in a device which does not include the needle rotation mechanism256 and vice versa.

As best seen in FIG. 8A, the hypodermic needle 218 has a proximal endconnected to the fluid distribution pathway 212 and a distal endconfigured for penetrating into the tissue 220 to be treated. In oneembodiment, the needles 218 may include micro-needles.

In one embodiment, the fluid injection device 202 includes needledeployment mechanism 216 for moving the hypodermic needle 218 from afully retracted position (FIG. 8A) in which the distal end of the needle218 is housed inside the solution injection member 202 to a fullyextended position (FIG. 8B).

As shown in FIGS. 9A-9C, the fluid injection device 202 may optionallybe provided with a tissue apposition mechanism which urges the device202 into firm apposition with the tissue 220 undergoing treatment.According to one embodiment the tissue apposition mechanism includes atleast one vacuum port 228 and a vacuum source 230 in fluid communicationwith the vacuum port 228. The vacuum port 228 may be defined in theneedle array 214 and/or the housing 108. In operation the tissueapposition surface 226A is pulled into apposition with the tissue 220when vacuum from the vacuum source 230 is transmitted through the vacuumport 228 to the tissue 220.

In some embodiments it may be desirable to provide a one-to-onerelationship between needles 218 and vacuum ports 228. Moreover, theneedle(s) 218 may be positioned within the vacuum port(s) 228. Thevacuum port 228 may define a recess or receptacle 229 such that thetissue 220 is at least partially pulled (sucked) into the recess 229 bythe vacuum force. Moreover, the needles 218 may be at least partiallyhoused within and deployed through the recess 229.

An optional flange 232 (show in dashed lines) may surround (skirt) theperiphery of the needles 218 (or 218A) to channel/contain the suctionforce. Alternatively, a separate flange 232A may surround (skirt) eachof the needles 218 (or 218A) to channel/contain the suction force.

It may be desirable to have one or more vacuum ports 228 spaced along aperiphery of the apposition surface 226A. Moreover, it may be desirableto include a central portion apposition surface 226A, which does notinclude any vacuum ports 228 (no suction zone). Alternatively, it may bedesirable to have vacuum ports confined to a central portion of theapposition surface 226A.

It should be appreciated that the liquid reservoir 102 and gas reservoir104, in each of the aforementioned embodiments may be replaced with acartridge 132 (FIG. 1D) containing a pre-measured amount of liquid andgas. The gas may be fully or partially dissolved in the fluid. In itssimplest form the cartridge 132 is simply a sealed container filled witha predetermined amount of gas and liquid, e.g., a soda can.

FIG. 10A shows an enhanced cartridge 106A (“Guinness can”), which may beused to replace the liquid reservoir 102, gas reservoir 104, and bubblegenerator 106 in each of the aforementioned embodiments. In thisembodiment, the cartridge 106A includes a hollow pressurized pod 134such as disclosed in U.S. Pat. No. 4,832,968, which is herebyincorporated by reference. Both the cartridge 106A and the pod 134contain a solution of gas and liquid under greater than ambient pressurewhich may for example be achieved by providing or introducing a dose ofliquid nitrogen into the solution before sealing the cartridge 106A.

The cartridge 106A includes a headspace 136, which is bounded between atop inner surface 138 and a gas-liquid interface 140. The pod 134includes a similar headspace 142, which is bounded between a top innersurface 144 and a gas-liquid interface 146.

The pod 134 includes a small opening or orifice 148, which enables thepressure within the headspace 136 of the cartridge 106A to reachequilibrium with the pressure within the headspace 142 of the pod 134.When a seal 150 of the cartridge 106A is pierced the pressure within theheadspace 136 rapidly reaches equilibrium with the ambient pressure. Inthe moments after seal 150 is pierced the pressure within the pod 134 isgreater than the pressure in the headspace 136 of the cartridge 106Abecause the orifice 148 restricts the rate of flow of solution out ofthe pod 134. A jet of solution forcefully streams out of the orifice 148into the solution within the cartridge 106A, which agitates and/orshears the solution within the cartridge causing some of the dissolvedbubbles to come out of solution thereby generating microbubbles in thesolution.

The pod 134 is preferably situated at or near the bottom of thecartridge 106A such that the orifice 148 is maintained below the liquidgas interface 140.

FIG. 10B is a block diagram showing the system 200 including cartridge106A in place of bubble generator 106.

The microbubble generator 106 may be mounted on (integrated with) thefluid injection device 202 thereby minimizing the distance that thesolution travels before being injected into the tissue. The liquidreservoir 102 and gas reservoir 104 (if provided) may be removablyconnected to the microbubble generator 106 as needed to generatemicrobubble solution. The injection device 202 may be manually supportedby the operator. Alternatively, the injection device 202 may besupported on an arm 302 (FIG. 11) which may include a counterbalance tofacilitate manipulation of the injection device 202.

FIG. 12A depicts a handpiece 300 which includes fluid injection device202 and which is coupled to the microbubble generator 106 (notillustrated) by a flexible conduit 236. This design minimizes the sizeand weight of handpiece 300 being handled by the operator since thehandpiece 300 does not include the microbubble generator 106.

FIG. 12B depicts a handpiece 300 using the cartridge 106A mounted on thefluid injection device 202. This embodiment minimizes the distance thatthe microbubble solution travels before being injected into the tissue.

According to one embodiment the system of the invention includes acontainer which may be an enclosed or sealed cartridge 106A or it may bean open container. If the container is sealed it includes a measuredamount of a solution. Obviously, if the container is not sealed thensolution may be freely added as needed.

The system includes a needle array including at least one needle. Theneedle array 214 being in fluid connection with the container.

The solution includes any of the solutions disclosed herein. Thesolution includes a liquid. The solution may further include a gas whichmay be partially or fully dissolved within the solution.

The container may be enclosed and the solution may be maintained atgreater than atmospheric pressure.

The needle array 214 includes at least one needle 218 which may be anyof the needles disclosed herein.

The aforementioned gas may include one or more gases selected from thegroup of air, oxygen, carbon dioxide, carbon dioxide, perfluoropropane,argon, hydrogen, Halothane, Desflurane, Sevoflurane, Isoflurane, andEnflurane.

The solution may include one or more of a vasoconstrictor, a surfactant,and an anesthetic. Moreover, the vasoconstrictor may include one or moreof Norepinephrine, Epinephrine, Angiotensin II, Vasopressin andEndothelin.

Optionally, the system may include refrigeration means for maintainingthe container at a predefined temperature range. Moreover, the containermay be thermally insulated.

The system may further include an ultrasound transducer apparatus 204for transmitting ultrasound waves to the tissue. Preferably, thetransducer apparatus 204 is operated in synchronism with the injectionof solution into the tissue.

The transducer apparatus 204 may transmit ultrasound energy at a firstsetting to facilitate the distribution, absorption and/or uptake ofsolution by the tissue, i.e., sonoporation.

Ultrasound parameters that enhance the distribution of the solutioninclude those conditions which create microstreaming, such as large dutycycle pulsed ultrasound (>10% duty cycle) or continuous wave ultrasoundat a range of frequencies from 500 kHz to 15 MHz, focused or unfocused,and a mechanical index less than 4. According to one embodiment themechanical index (MI) falls within the range 0.5≦MI≦4. According toanother embodiment the mechanical index falls within the range0.5≦MI≦1.9.

Sonoporation leading to increased absorption and/or uptake of thesolution in the tissue can be generated by pulsed wave or continuouswave ultrasound, at a range of frequencies from 500 kHz to 15 MHz,focused or unfocused and medium to high mechanical index (MI>1.0). Thepreferred embodiment is pulsed wave ultrasound at a frequency of 500kHz, unfocused, with high mechanical index (MI>1.9) in order toreproducibly create pores that are temporary or longer lasting pores.

The transducer apparatus 204 may transmit ultrasound energy at a secondsetting to facilitate the generation of bubbles by bringing dissolvedgas out of solution, i.e., stable cavitation.

Ultrasound parameters for stable cavitation such as large duty cyclepulsed ultrasound (>10% duty cycle) or continuous wave ultrasound at arange of frequencies from 2 MHz to 15 MHz, focused or unfocused, and amechanical index (MI).05≦MI≦2.0.

The transducer apparatus 204 may transmit ultrasound energy at a thirdsetting to facilitate transient cavitation, i.e., popping bubbles.

Ultrasound parameters for transient cavitation at a range of frequenciesfrom 500 kHz to 2 MHz, focused or unfocused, and a mechanical index (MI)greater than 1.9. The duty cycle required for transient cavitation maybe very low, and the preferred embodiment is a wideband pulse (1 to 20cycles) transmitted at a duty cycle less than 5%.

The transducer apparatus 204 may include any of the transducersdisclosed herein, and may be operably connected to the needle array 214.

The transducer apparatus 204 may transmit ultrasound energy at a fourthfrequency range to facilitate the pushing of bubbles within the tissueby acoustic streaming and/or acoustic radiation force.

Ultrasound Acoustic Streaming and Radiation Force

Sound propagating through a medium produces a force on particlessuspended in the medium, and also upon the medium itself. Ultrasoundproduces a radiation force that is exerted upon objects in a medium withan acoustic impedance different than that of the medium. An example is ananoparticle in blood, although, as one of ordinary skill willrecognize, ultrasound radiation forces also may be generated onnon-liquid core carrier particles. When the medium is a liquid, thefluid translation resulting from application of ultrasound is calledacoustic streaming.

The ability of radiation force to concentrate microbubbles in-vitro andin-vivo has been demonstrated, e.g., Dayton, et al., Ultrasound in Med.& Biol., 25(8):1195-1201 (1999). An ultrasound transducer pulsing at 5MHz center frequency, 10 kHz pulse repetition frequency (“PRF”), and 800kPa peak pressure, has been shown to concentrate microbubbles against avessel wall in-vivo, and reduce the velocity of these flowing agents anorder of magnitude. In addition, the application of radiation toconcentrate drug delivery carrier particles and the combined effects ofradiation force-induced concentration and carrier fragmentation has beendemonstrated. See U.S. patent application Ser. No. 10/928,648, entitled“Ultrasonic Concentration of Drug Delivery Capsules,” filed Aug. 26,2004 by Paul Dayton et al., which is incorporated herein by reference.

Acoustic streaming and optionally radiation force may be used to “push”or concentrate microbubbles injected into the tissue along a cellmembrane. Notably, acoustic streaming has previously been used to pushor concentrate carrier particles within a blood vessel. In contrast, thepresent invention utilizes acoustic streaming to push bubbles withinsubcutaneous tissue to concentrate the bubble against the walls of cellsto be treated.

According to one aspect of the present invention, a solution containingmicrobubbles is injected into subcutaneous tissue or a solutioncontaining dissolved gas is injected into subcutaneous tissue andinsonated to bring the gas out of solution thereby generating bubbleswithin the subcutaneous tissue. The bubbles are pushed against the cellwalls using acoustic streaming, and then insonated to induce transientcavitation to enhance the transport of the solution through the cellmembrane and/or mechanically disrupt the cell membrane to selectivelylyse cells.

The ultrasound parameters useful for inducing acoustic streaming includeultrasound waves having center frequencies about 0.1-20 MHz, at anacoustic pressure about 100 kPa-20 MPa, a long cycle length (e.g.,about >10 cycles and continuous-wave) OR a short cycle length (e.g.,about <10 cycle), and high pulse repetition frequency (e.g., about >500Hz). The specific parameters will depend on the choice of carrierparticle, as detailed further below, and can be readily determined byone of ordinary skill in the art.

According to one embodiment, the transducer apparatus 204 includes asingle transducer capable of operating a plurality of operating modes tofacilitate stable cavitation, transient cavitation, acoustic streaming,and sonoporation. According to another embodiment, the transducerapparatus 204 includes first and second transducers with firsttransducer optimized for popping bubbles (transient cavitation) and thesecond transducer optimized for bringing dissolved gas out of solution(stable cavitation) and/or pushing the bubbles using acoustic radiationforce.

The transducer apparatus may produce focused, unfocused, or defocusedultrasound waves. Focused ultrasound refers to generally convergingultrasound waves, unfocused ultrasound refers to generally parallelultrasound waves and defocused ultrasound wave refers to generallydiverging ultrasound waves.

However, according to a preferred embodiment, the transducer apparatus204 selectively produces unfocused and/or defocused ultrasound waves.For example, it may be desirable to utilize unfocused waves duringtransient cavitation, and defocused waves during stable cavitation. Tothis end the transducer apparatus may include a flat transducer, i.e., atransducer having a generally planar acoustic wear layer (acousticwindow) for producing unfocused ultrasound waves (nonconverging waves)and/or a convex transducer, i.e., a transducer having a convex acousticwear layer for producing defocused ultrasound waves (diverging waves).

As will be appreciated by one of ordinary skill in the art, there aremany different configurations for the ultrasound apparatus. FIG. 14depicts an embodiment in which the transducer apparatus 204 includes aninner transducer 204A and an outer transducer 204B. In the illustratedembodiment, the inner transducer 204A has a convex shaped acoustic wearlayer for producing defocused waves 205A, and the outer transducer 204Bhas a planar shaped acoustic wear layer for producing unfocused waves205B. However, both of the inner and outer transducers 204A and 204B maybe planar or both may be convex. Still further, one or both of the innerand outer transducers may be concave, i.e., may have a concave acousticwear layer for producing focused waves. Thus, the ultrasound apparatus204 may include any combination of focused, unfocused, and defocusedtransducers.

The inner and outer transducers depicted in FIG. 14 are both circularand the outer transducer surrounds (encircles) the inner transducer.However, other configurations are contemplated and fall within the scopeof the invention. According to a presently preferred embodiment, theinner transducer is used to produce stable cavitation and the outertransducer is used to create transient cavitation. However, the relativepositions may be swapped with the inner transducer producing transientcavitation and the outer transducer producing stable cavitation.

The ultrasound apparatus 204 illustrated in FIG. 14 includes a needlearray 214 of the type described elsewhere in this disclosure. Thetransducer apparatus 204 of FIG. 14 may be incorporated in any of theembodiments disclosed herein which include an ultrasound transducer.Notably, the transducer apparatus 204 may be incorporated in system 200.

It should be noted that the transducer apparatus 204 may include one ormore arrays of transducers. For example, the transducer apparatus mayinclude an array of transducers for stable cavitation and/or an array oftransducers for transient cavitation.

According to another aspect of the present invention, a solution whichmay or may not include microbubbles is injected into subcutaneoustissue. The solution is pushed against the cell walls using acousticstreaming, and then the subcutaneous tissue is insonated to inducesonoporation and facilitate the uptake/absorption of solution by thetissue. Solution is injected an insonated using a system such as system200 depicted in FIG. 13 which does not include a bubble generator 100.Absorption of the solution preferably results in cell lysis.

As described in U.S. Utility patent application Ser. No. 11/292,950filed Dec. 2, 2005, the ultrasound energy from ultrasound generator 206is applied to the tissue 220 via ultrasound transducer 204. Ultrasoundcontrol unit 208 controls the various ultrasound parameters andgenerally controls the supply of ultrasound by generator 206.Preferably, ultrasound control unit 208 communicates with the injectioncontrol unit 210 to synchronize the application or ultrasound energywith the injection of fluid. It may for example be desirable to quicklyapply energy to the tissue before the microbubbles dissipate or areabsorbed by the tissue.

The ultrasound transducer 204 is preferably configured to deliverunfocused ultrasound at an intensity and pressure sufficient tononinvasively cavitate the microbubbles within tissue thereby causingcell lysis. The intensity and pressure of the ultrasound applied to thetissue is preferably selected to minimize the heating of tissue and inparticular avoid burning the patient's skin. The transducer 204 mayinclude a thermocouple 238 or the like to monitor the temperature of thetransducer 204.

In at least one embodiment the liposculpture system 200 (FIG. 2)includes an ID reader 250 (shown in dashed lines), and the needle array214 includes an identifier 252 (shown in dashed lines), which uniquelyidentifies the needle array 214. The ID reader 250 reads the identifier252, and preferably authenticates or verifies the needle array 214. Theidentifier 252 may contain information identifying the characteristicsof the needle array 214 such as length and gauge of needles. Theidentifier 252 may further include identifying information which may beused to track the number of injection cycles (needle deployments) or usetime for a given array 214.

The reader 250 preferably communicates with the injection control unit210. The injection control unit 210 may count the number of injectioncycles that a given needle array 214 has been used, and may warn theoperator if the number exceeds a threshold number. The injection controlunit 250 may use information stored on the identifier 252 to adjust theinjection depth or injection flow rate. The injection control unit 210may further inhibit usage of a needle array if it cannot authenticate,verify or read the identifier 252.

The identifier 252 may be a barcode label, a radio frequency tag, smartchip or other machine-readable medium such as known in the art.

The ultrasound transducer 204 may also include an identifier 252. Theidentifier 252 may be used to store information identifying thecharacteristics of the transducer 204, which is used by the ultrasoundcontrol unit 208 in setting or verifying the treatment settings. Theultrasound control unit 208 may inhibit insonation if it cannotauthenticate, verify or read the identifier 252.

As described above, the transducer 204 may be integrated with the needlearray 214 in which case a single identifier 252 may store informationdescribing characteristics of both the needle(s) 218 and the transducer204. The ultrasound control unit 208 may use information on theidentifier 252 to track the amount of time the identified ultrasoundtransducer 204 has been operated and at what power levels, and mayinhibit insonation if the accumulated insonation time exceeds athreshold value.

The constituent components of the device 100 may be formed of anysterilizable, biocompatible material. Moreover, some or all of thecomponents may be disposable, i.e., manufactured for single-patient use,to minimize potential cross-contamination of patients. The needle array214 is preferably a disposable component, as the needles 218 will likelydull with use.

One or more optical or pressure sensors 254 (FIG. 5) may be provided tomeasure pressure exerted on the handpiece 300 (FIG. 12A) when thehandpiece is placed in abutment with the tissue. The pressure sensor(s)254 may provide a safety interlock function to prevent inadvertentdeployment of the needle array 214 and/or actuation of the transducer204 unless pressure is detected as the handpiece 300 is placed inabutment with the tissue. If two or more pressure sensors 254 areprovided the injection of solution and/or insonation may be inhibitedunless each of the measured pressure values fall within a predefinedwindow and/or so long as the difference between any given two measuredpressure values is less than a threshold value. The pressure sensor(s)254 may, for example, be provided on the needle array 214 (FIG. 4) or onthe fluid injection device 202 (not illustrated). Alternatively, othersensing means, possibly optical or capacitive, may be used to detectproper positioning of the needle array against the tissue to be treated.

It may be advantageous to couple the needles 218 with the ultrasoundtransducer 204 such that ultrasound is transmitted through the needle(s)218 to the tissue. Applying ultrasound in this manner may facilitatetargeted cavitation and/or may facilitate penetration of the needle(s)218 into the tissue.

FIG. 13 is a block diagram of a system 200 for a fat lysing systemaccording to the present invention. The system 200 is identical to thesystem 200 of FIG. 2 but excludes the bubble generator 100. Moreover,the ultrasound transducer 204, ultrasound generator 206, and ultrasoundcontrol unit 208 are shown in dashed lines to indicate that these areoptional components. The system 500 may be used to inject a fat lysingsolution (as will be described below in greater detail) with or withoutthe use of ultrasound.

According to one embodiment, the fat lysing solution includesepinephrine as its active ingredient. The epinephrine may be combinedwith an aqueous solution, isotonic saline, normal saline, hypotonicsaline, hypotonic solution, or a hypertonic solution. The solution mayoptionally include one or more additives/agents to raise the pH (e.g.,sodium bicarbonate) or a buffering agent such those listed in Table 5above or other buffering agents such as known in the art.

According to a presently preferred embodiment the fat lysing solutionincludes epinephrine in hypotonic buffered saline.

The inclusion of ultrasound in system 200 may facilitate the absorptionand/or distribution of the fat lysing solution. The inclusion ofultrasound in system 200 may facilitate the absorption and/ordistribution of the fat lysing solution. More particularly, theultrasound may be used to enhance the distribution, absorption, and/oruptake of the solution in the tissue by permanently or temporarilyopening pores in the cell membrane (sonoporation), generatingmicrostreaming in the solution, or locally heating the solution or thetissue. According to one aspect of the invention, the ultrasoundgenerator 206 may be operated at a first setting to facilitatedistribution of the solution and then it may be operated at a secondsetting to facilitate absorption. The sonoporation may be reversible orirreversible.

The system 200 may include an optional ultrasound transducer 258 forvibrating the needles 218 to facilitate tissue penetration and/or aneedle rotation mechanism 256 which may be used in conjunction withside-firing needles 218 to facilitate even distribution of the solution.The same transducer apparatus 204 used to facilitate absorption and/ordistribution of the solution may be used to facilitate tissuepenetration thereby eliminating the need for a separate transducer 258.

The system 200 may include any or all of the features described in thisdisclosure including means for selectively adjusting the amount ofsolution injected by each of the needles 218 and/or the rate or pressureat which the solution is injected into the tissue. Still further thesystem 200 may include the selective adjustment of the injection depthand/or the tissue apposition mechanism as described above.

Mode of Operation/Method of Use

According to a first mode of operation, solution is percutaneouslyinjected into subcutaneous tissue, and the tissue is insonated at afirst ultrasound setting to distribute the solution. Once the solutionhas been distributed the tissue is insonated at a second setting toinduce sonoporation thereby inducing cell lysis. According to this modeof operation the solution need not contain microbubbles as they do notcontribute to cell lysis. To increase the efficacy of this mode ofoperation it is recommended to repeat the injection and insonation ofthe tissue through 10 to 50 cycles.

According to a second mode of operation, a solution containingmicrobubbles is percutaneously injected into subcutaneous tissue, andthe tissue is insonated at a first ultrasound setting to distribute thesolution and/or push the microbubbles against the cell walls. Thereafterthe tissue is insonated at a second setting (for between 1 millisecondand 1 second) to induce transient cavitation inducing cell lysis. Toincrease the efficacy of this mode of operation it is recommended torepeat the injection and insonation of the tissue through 10 to 50cycles.

It should be appreciated that it is important to synchronize the timingof the insonation. Notably, the microbubbles will be absorbed by thetissue and/or go into solution within a relatively short period of time.Thus, it is important to distribute the microbubbles (using acousticradiation force) and induce transient cavitation within a relativelyshort time after the solution has been injected into the subcutaneoustissue.

According to a presently preferred embodiment, the tissue is insonatedto facilitate distribution of the microbubble solution through acousticradiation force and/or microstreaming occurs simultaneously as thesolution is injected into the tissue or within a very short amount oftime afterward. The injection of a small amount of the microbubblesolution takes approximately 200 milliseconds and insonation to inducedistribution through acoustic radiation force takes between 1millisecond and 1 second. Next, the tissue is insonated to inducetransient cavitation for approximately 400 milliseconds.

According to a third mode of operation, a solution containing dissolvedgas, i.e., dissolved gas bubbles is percutaneously injected intosubcutaneous tissue, and the tissue is insonated at a first ultrasoundsetting to bring the bubbles out of solution (for between 100microseconds and 1 millisecond) followed immediately by insonation at asecond setting (for between 1 millisecond and 1 second) to distributethe solution and/or push the microbubbles against the cell walls.Thereafter the tissue is insonated at a third setting (for between 100microseconds and 1 second) to induce transient cavitation inducing celllysis. To increase the efficacy of this mode of operation it isrecommended to repeat the injection and insonation of the tissue through10 to 50 cycles.

It should be appreciated that it is important to synchronize the timingof the insonation. Notably, the microbubbles will be absorbed by thetissue and/or go into solution within a relatively short period of time.Thus, it is important to distribute the microbubbles (using acousticradiation force) and induce transient cavitation within a relativelyshort time after the bubbles have been brought out of solution.

According to a presently preferred embodiment, the tissue is insonatedto induce stable cavitation and bring the bubbles out of solution afterthe solution has been injected into the subcutaneous tissue.Satisfactory stable cavitation results have been achieved by insonatingfor approximately 100 microseconds. Thereafter the tissue is insonatedto facilitate distribution of the microbubble solution through acousticradiation force and/or microstreaming occurs. Insonating for between 1millisecond and 1 second is required to distribute the microbubbles.Immediately thereafter the tissue is insonated to induce transientcavitation for approximately 400 milliseconds.

The invention may be combined with other methods or apparatus fortreating tissues. For example, the invention may also include use ofskin tightening procedures, for example, ThermaCool™ available fromThermage Corporation located in Hayward, Calif., Cutera Titan™ availablefrom Cutera, Inc. located in Brisbane, Calif., or Aluma™ available fromLumenis, Inc. located in Santa Clara, Calif.

The invention may be embodied in other forms without departure from thespirit and essential characteristics thereof. The embodiments describedtherefore are to be considered in all respects as illustrative and notrestrictive. Although the present invention has been described in termsof certain preferred embodiments, other embodiments that are apparent tothose of ordinary skill in the art are also within the scope of theinvention. Accordingly, the scope of the invention is intended to bedefined only by reference to the appended claims.

1-5. (canceled)
 6. A device for generating microbubbles in a gas andliquid mixture and injection device, said device comprising: a housingdefining a mixing chamber and mixing a solution contained in said mixingchamber to generate microbubbles in the solution; a needle arrayremovably attached to the housing and in fluid connection with saidmixing chamber, said needle array including a plurality of non-vibratingsolution injection needles operably connected to the mixing chamber,said solution injection members needles being substantially equallyspaced apart and configured to percutaneously inject the microbubblesolution into a treatment area located in a subcutaneous tissue between3 mm and 15 mm below the dermis; and at least one pressure sensor formeasuring tissue apposition pressure, said pressure sensor being mountedon one of the housing and the needle array, wherein the device isconfigured to infuse a substantially uniform distribution of themicrobubble solution in the treatment area, and wherein the microbubblesolution is configured to produce subcutaneous cavitational bioeffectsin the treatment area without significant thermal effects to thesubcutaneous tissue and the dermis when subjected to unfocused acousticwaves from a point above and external to the dermis.
 7. The device ofclaim 6, further comprising: a deployment means, wherein deployment ofsaid needles is inhibited if a measured apposition pressure value fallsbeneath an initial threshold value or exceeds a secondary thresholdvalue.
 8. The device of claim 6, further comprising: a deployment means;and, two pressure sensors, wherein deployment of said needles isinhibited if a difference in measured apposition pressure values betweenany two sensors exceeds a threshold value.
 9. The device of claim 8,wherein deployment of said needles is inhibited if a measured appositionpressure values falls beneath an initial threshold value or exceeds asecondary threshold value.
 10. The device of claim 6, wherein saidneedles comprise a needle having a through-bore, the needle having atexture.